Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake

Yaxia Yuan; Pamela M. Quizon; Wei Lun Sun; Jianzhuang Yao; Jun Zhu; Chang Guo Zhan

doi:10.1038/srep27314

Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake

Yaxia Yuan, Pamela M. Quizon, Wei Lun Sun, Jianzhuang Yao, Jun Zhu, Chang Guo Zhan

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

HIV-1 Tat plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting neurotransmission including dopamine uptake by human dopamine transporter (hDAT). Previous studies have demonstrated that HIV-1 Tat directly binds to hDAT and some amino-acid mutations that attenuate the hDAT-Tat binding also significantly decreased dopamine uptake activity of hDAT. This combined computational-experimental study demonstrates that histidine-547 (H547) of hDAT plays a crucial role in the hDAT-Tat binding and dopamine uptake by hDAT, and that the H547A mutation can not only considerably attenuate Tat-induced inhibition of dopamine uptake, but also significantly increase the V_max of hDAT for dopamine uptake. The finding of such an unusual hDAT mutant capable of both increasing the V_max of hDAT for dopamine uptake and disrupting the hDAT-Tat binding may provide an exciting knowledge basis for development of novel concepts for therapeutic treatment of the HAND.

Original language	English
Article number	27314
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep27314
State	Published - Jun 2 2016

Bibliographical note

Funding Information:
This work was supported in part by the NIH (grants R01 DA035714, R01 DA035552, R01 DA032910, and R01 DA025100) and the NSF (grant CHE-1111761).

Funding

This work was supported in part by the NIH (grants R01 DA035714, R01 DA035552, R01 DA032910, and R01 DA025100) and the NSF (grant CHE-1111761).

Funders	Funder number
National Science Foundation Arctic Social Science Program	CHE-1111761
National Institutes of Health (NIH)	R01 DA025100, R01 DA035714, R01 DA032910
National Institute on Drug Abuse	R01DA035552

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title = "Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake",

abstract = "HIV-1 Tat plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting neurotransmission including dopamine uptake by human dopamine transporter (hDAT). Previous studies have demonstrated that HIV-1 Tat directly binds to hDAT and some amino-acid mutations that attenuate the hDAT-Tat binding also significantly decreased dopamine uptake activity of hDAT. This combined computational-experimental study demonstrates that histidine-547 (H547) of hDAT plays a crucial role in the hDAT-Tat binding and dopamine uptake by hDAT, and that the H547A mutation can not only considerably attenuate Tat-induced inhibition of dopamine uptake, but also significantly increase the Vmax of hDAT for dopamine uptake. The finding of such an unusual hDAT mutant capable of both increasing the Vmax of hDAT for dopamine uptake and disrupting the hDAT-Tat binding may provide an exciting knowledge basis for development of novel concepts for therapeutic treatment of the HAND.",

author = "Yaxia Yuan and Quizon, \{Pamela M.\} and Sun, \{Wei Lun\} and Jianzhuang Yao and Jun Zhu and Zhan, \{Chang Guo\}",

note = "Funding Information: This work was supported in part by the NIH (grants R01 DA035714, R01 DA035552, R01 DA032910, and R01 DA025100) and the NSF (grant CHE-1111761).",

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AU - Quizon, Pamela M.

AU - Sun, Wei Lun

AU - Yao, Jianzhuang

AU - Zhu, Jun

AU - Zhan, Chang Guo

N1 - Funding Information: This work was supported in part by the NIH (grants R01 DA035714, R01 DA035552, R01 DA032910, and R01 DA025100) and the NSF (grant CHE-1111761).

PY - 2016/6/2

Y1 - 2016/6/2

N2 - HIV-1 Tat plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting neurotransmission including dopamine uptake by human dopamine transporter (hDAT). Previous studies have demonstrated that HIV-1 Tat directly binds to hDAT and some amino-acid mutations that attenuate the hDAT-Tat binding also significantly decreased dopamine uptake activity of hDAT. This combined computational-experimental study demonstrates that histidine-547 (H547) of hDAT plays a crucial role in the hDAT-Tat binding and dopamine uptake by hDAT, and that the H547A mutation can not only considerably attenuate Tat-induced inhibition of dopamine uptake, but also significantly increase the Vmax of hDAT for dopamine uptake. The finding of such an unusual hDAT mutant capable of both increasing the Vmax of hDAT for dopamine uptake and disrupting the hDAT-Tat binding may provide an exciting knowledge basis for development of novel concepts for therapeutic treatment of the HAND.

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Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake

Abstract

Bibliographical note

Funding

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UN SDGs

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